In the last several years a number of 2-(substituted phenyl)alkanoic acid derivatives have been discovered and developed for use as anti-inflammatory, analgesic and anti-pyretic drugs, for use in treating mammals, including humans. Many of these drugs are described in the medicinal and patent literature. Examples of the more significant of such compounds which are being commercialized or studied for possible commercialization and which can be prepared by the process of this invention include 2-(4-isobutylphenyl)propionic acid, now known generically as ibuprofen, 2-(2-fluoro-4-phenylphenyl)propionic acid, now known generically as flurbiprofen (see U.S. Pat. No. 3,755,427) and 2-(4-phenylphenyl)propionic acid, and a number of others.
A number of chemical process routes have been described for making these alkanoic acid derivative drug compounds. Most of such processes have involved the use of aromatic ring moiety reactants. For example, processes have been described for preparing the 2-(substituted phenyl)propionic acids (a) from aromatic clycidonitriles (see Argentine Pat. Nos. 198,097 and 198,595 ), (b) from aromatic glycidyl esters (see German Offenlegungsshrift No. 2,404,159, published Aug. 29, 1974), (c) from aromatic alkyl cyanides and by a variety of other process routes, all of which involve the use of an aromatic moiety. See, for example, U.S. Pat. 3,600,437 for a description of a number of those processes.
More recently Belgian Pat. No. 820,267 described a process for preparing p-isobutyl-hydratropic acid (ibuprofen) by treating an aliphatic compound of the formula ##STR1## where each R is a C.sub.1 to C.sub.5 -alkyl, with a strong acid aqueous solution at 200 to 240.degree. C., or in a dry state with a strong acid salt and an organic base for from 30 minutes to 3 hours. That Belgian Patent also indicates that its formula (ll) compound need not be isolated before acid treatment but can be obtained in the crude product form by reacting the vinyl-isobutyl-ketone with alkyl .alpha.-acetyl-.alpha.-methylsuccinate, or by reaction of an acetoacetic acid ester with an alkyl .alpha.-halopropionate and then with the vinyl-isobutyl-ketone.
That Belgian Patent also refers to prior processes and to some prior patents, including British Patent No. 1,265,800 which is said to disclose the synthesis of methyl or ethyl 2-(4-isobutyl-2-oxocyclohex-3-enyl)propionate in some undisclosed yield. The Belgian Patent No. 820,267 indicates that when they repeated the pertinent experiments of the British Pat. No. 1,265,800 they obtained yields of less than 5 percent; and concluded the process for preparing p-isobutyl-hydratropic acid (ibuprofen) as described in British Pat. No. 1,265,800 had no industrial application. The Belgian Pat. points out that the advantages of its described process for preparing 2-(4-isobutyl-2-oxo-3-cyclohexenyl)propionic acid intermediate is that it does not require the use of expensive and dangerous reagents such as silver nitrate or cyanide ion. That Belgian Pat. process for the production of ibuprofen from 2-(4-isobutyl-2-oxo-3-cyclohexenyl)propionic acid is based upon the aromatization which occurs when a dialkyl-.alpha.-acetyl-.alpha.-[(5-methyl-3-oxo)hexyl]-.alpha.'-methylsucc inate is heated to temperatures of about 200 to 240.degree. C. with strong acid, but the Belgian Pat. process requires the use of a polmerizable intermediate.
The British Pat. No. 1,265,800 process requires the use of corrosive materials. Persons skilled in this process art are searching for improved processes for making these valuable drug compounds while avoiding the use of polymerizable intermediates or corrosive materials.